Antisense nucleic acid for treating amyotrophy

• US 10,563,199 B2
• Filed: 09/16/2016
• Issued: 02/18/2020
• Est. Priority Date: 09/16/2015
• Status: Active Grant

• Current Assignee: Kawasaki Gakuen Educational Foundation, Nippon Shinyaku Company Limited
• Original Assignee: Nippon Shinyaku Company Limited
• Inventors: Nakagawa, Shinichiro, Nagata, Seigo, Sunada, Yoshihide, Ohsawa, Yutaka, Nishimatsu, Shin-ichiro
• Primary Examiner(s): Whiteman, Brian
• Application Number:
  US15/759,305
• Publication Number:
  US 20180251760A1
• Time in Patent Office: 1,250 Days
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/31 of the backbone
• CPC Class Codes: C12N 2310/32 of the sugar
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/3519 Fusion with another nucleic acid
• CPC Class Codes: C12N 2320/33 Alteration of splicing

Abstract

There has been a demand for a novel antisense nucleic acid or the like capable of inhibiting myostatin at the mRNA level. The present invention provides a specific antisense oligomer which allows exon 2 skipping in the myostatin gene or induces degradation of mRNA of the myostatin gene.

Claims

1. An antisense oligomer or pharmaceutically acceptable salt or hydrate thereof, wherein the antisense oligomer consists of any one nucleotide sequence selected from the group consisting of SEQ ID NO:

103 (NMS-48), SEQ ID NO;

116 (NMS-89), SEQ ID NO;

117 (NMS-90), SEQ ID NO;

120 (NMS-93), SEQ ID NO;

128 (NMS-101), SEQ ID NO;

131 (NMS-104), SEQ ID NO;

136 (NMS-113), SEQ ID NO;

137 (NMS-117), SEQ ID NO;

140 (NMS-123), SEQ ID NO;

145 (NMS-136), SEQ ID NO;

146 (NMS-139), SEQ ID NO;

147 (NMS-140), SEQ ID NO;

148 (NMS-141), SEQ ID NO;

149 (NMS-142), SEQ ID NO;

152 (NMS-145), SEQ ID NO;

155 (NMS-148), SEQ ID NO;

156 (NMS-149), SEQ ID NO;

157 (NMS-150), SEQ ID NO;

159 (NMS-152), SEQ ID NO;

162 (NMS-156), SEQ ID NO;

163 (NMS-157), SEQ ID NO;

165 (NMS-162), SEQ ID NO;

166 (NMS-163), SEQ ID NO;

167 (NMS-164), SEQ ID NO;

168 (NMS-166), SEQ ID NO;

169 (NMS-167), SEQ ID NO;

170 (NMS-168), SEQ ID NO;

171 (NMS-169), SEQ ID NO;

176 (NMS-174), SEQ ID NO;

177 (NMS-175), SEQ ID NO;

178 (NMS-176), SEQ ID NO;

179 (NMS-177), SEQ ID NO;

180 (NMS-178), SEQ ID NO;

183 (NMS-181), SEQ ID NO;

187 (NMS-185), SEQ ID NO;

189 (NMS-188), SEQ ID NO;

190 (NMS-189), SEQ ID NO;

191 (NMS-190), SEQ ID NO;

192 (NMS-191), SEQ ID NO;

193 (NMS-192), SEQ ID NO;

196 (NMS-195), SEQ ID NO;

199 (NMS-198), SEQ ID NO;

200 (NMS-199), SEQ ID NO;

201 (NMS-200), SEQ ID NO;

203 (NMS-202), SEQ ID NO;

204 (NMS-203), SEQ ID NO;

206 (NMS-206), SEQ ID NO;

208 (NMS-208), SEQ ID NO;

212 (NMS-212), SEQ ID NO;

213 (NMS-213), SEQ ID NO;

214 (NMS-214), SEQ ID NO;

215 (NMS-215), SEQ ID NO;

217 (NMS-217), SEQ ID NO;

225 (NMS-225), SEQ ID NO;

226 (NMS-228), SEQ ID NO;

228 (NMS-230), SEQ ID NO;

229 (NMS-231), SEQ ID NO;

231 (NMS-233), SEQ ID NO;

232 (NMS-234), SEQ ID NO;

233 (NMS-235), SEQ ID NO;

236 (NMS-240), SEQ ID NO;

237 (NMS-241), SEQ ID NO;

240 (NMS-244), SEQ ID NO;

243 (NMS-247), SEQ ID NO;

244 (NMS-248), SEQ ID NO;

245 (NMS-249), SEQ ID NO;

246 (NMS-250), SEQ ID NO;

247 (NMS-251), SEQ ID NO;

248 (NMS-252), SEQ ID NO;

252 (NMS-256), SEQ ID NO;

261 (NMS-272), SEQ ID NO;

273 (NMS-284), SEQ ID NO;

274 (NMS-285), SEQ ID NO;

275 (NMS-286), SEQ ID NO;

277 (NMS-297), SEQ ID NO;

95 (NMS-38), SEQ ID NO;

96 (NMS-39), SEQ ID NO;

107 (NMS-66), SEQ ID NO;

223 (NMS-223), SEQ ID NO;

234 (NMS-238), SEQ ID NO;

235 (NMS-239), SEQ ID NO;

242 (NMS-246), SEQ ID NO;

249 (NMS-253), SEQ ID NO;

250 (NMS-254), SEQ ID NO;

251 (NMS-255), SEQ ID NO;

257 (NMS-268), SEQ ID NO;

290 (NMS-280), SEQ ID NO;

291 (NMS-281), SEQ ID NO;

292 (NMS-282), SEQ ID NO;

293 (NMS-288), SEQ ID NO;

294 (NMS-289), SEQ ID NO;

295 (NMS-290), SEQ ID NO;

297 (NMS-292), SEQ ID NO;

298 (NMS-293), SEQ ID NO;

299 (NMS-294), SEQ ID NO;

300 (NMS-295), SEQ ID NO;

301 (NMS-298), SEQ ID NO;

302 (NMS-299), SEQ ID NO;

303 (NMS-300), SEQ ID NO;

304 (NMS-302), and SEQ ID NO;

305 (NMS-303).

2. The antisense oligomer or pharmaceutically acceptable salt or hydrate thereof according to claim 1, wherein the antisense oligomer is an oligonucleotide.

3. The antisense oligomer or pharmaceutically acceptable salt or hydrate thereof according to claim 2, wherein the oligonucleotide comprises at least one nucleotide having a modified sugar moiety and/or a modified phosphate bond moiety.

4. The antisense oligomer or pharmaceutically acceptable salt or hydrate thereof according to claim 3, wherein the modified sugar moiety is a ribose in which the —

OH group at the 2′

-position is substituted with any group selected from the group consisting of;

OR, R, R′

OR, SH, SR, NH₂, NHR, NR₂, N₃, CN, F, Cl, Br, and I (wherein R represents alkyl or aryl, and R′

represents alkylene).

5. The antisense oligomer or pharmaceutically acceptable salt or hydrate thereof according to claim 3, wherein the modified phosphate bond moiety is any one selected from the group consisting of:

a phosphorothioate bond, a phosphorodithioate bond, an alkylphosphonate bond, a phosphoroamidate bond, and a boranophosphate bond.

6. The antisense oligomer or pharmaceutically acceptable salt or hydrate thereof according to claim 1, wherein the antisense oligomer is a morpholino oligomer.

7. The antisense oligomer or pharmaceutically acceptable salt or hydrate thereof according to claim 6, wherein the morpholino oligomer is a phosphorodiamidate morpholino oligomer.

8. The antisense oligomer or pharmaceutically acceptable salt or hydrate thereof according to claim 6, wherein the 5′

-terminal end of the morpholino oligomer is any one of the groups represented by chemical formulae (1) to (3) shown below;

9. The antisense oligomer or pharmaceutically acceptable salt or hydrate thereof according to claim 1, wherein the antisense oligomer consists of any one nucleotide sequence selected from the group consisting of:

SEQ ID NO;

171 (NMS-169), SEQ ID NO;

192 (NMS-191), SEQ ID NO;

245 (NMS-249), and SEQ ID NO;

231 (NMS-233).

10. A method for treating an amyotrophic disease or a muscle wasting disease, which comprises administering a subject in need of treating the amyotrophic disease or the muscle wasting disease with a therapeutically effective amount of the antisense oligomer or pharmaceutically acceptable salt or hydrate thereof according to claim 1.

11. The method according to claim 10, wherein the amyotrophic disease or the muscle wasting disease is muscular dystrophy.

12. The method according to claim 10, wherein the subject is a human subject.